1. Field of the Invention
The present invention relates to the treatment of ocular hypertension with alternate administration of (a) a .beta.-adrenergic blocker and (b) a prostanoic acid compound with an improved efficiency.
The compounds used as the component (b) in the present invention are prostaglandin analogues.
2. Information of Prior Art
It is well known that the production and effluence of the aqueous humor, which are the important factors for the circulation of the aqueous humor, and hence the intraocular pressure as the results thereof, vary with the circadian rhythm. Generally, in humans, the phase in which the aqueous humor production enhances is the daytime, during which the production of the aqueous humor is facilitated and the intraocular pressure rises. On the other hand, the phase in which the aqueous humor production suppresses is the night, during which the production of the aqueous humor is inhibited and the intraocular pressure falls. In contrast, in rabbits, the phase in which the aqueous humor production enhances is the night and the phase in which the aqueous humor production supresses is the daytime.
This circadian rhythm of the intraocular pressure is observed not only in healthy humans but also in subjects of ocular hypertension such as with glaucoma and a possibility that a relatively big variation in the intraocular pressure of hypertensive subjects may be an aggravating factor to the condition of disease has been noted. Accordingly, there is a continuous need for the development of an improved method for treatment of ocular hypertension in which the intraocular pressure is effectively controlled taking the circadian rhythm of ocular tension in the hypertensive subjects into consideration.
The .beta.-adrenergic blockers are the most widely used drugs for the treatment of glaucoma and ocular hypertension. In a report studying a relation between the circadian rhythm of intraocular pressure and the ocular hypotensive activity of Timolol, a .beta.-adrenergic blocker, it was observed that the activity of Timolol was significant in the enhancement phase of aqueous humor production, i.e. daytime in humans and night in rabbits, but negligible in the suppression phase of aqueous humor production, i.e. night in humans and daytime in rabbits. This fact indicates that there may be a possibility in which apparent (or observable) effect of .beta.-adrenergic blockers such as Timolol is high at the enhancement phase of aqueous humor production and low at the suppression phase of aqueous humor production. However, in view of the facts that most of cause for the ocular hypertension lies in the inhibition of effluence of the aqueous humor and that controlling of the ocular hension is important for the treatment of ocular hypertension also in the suppression phase of aqueous humor production, it is considered that treating the ocular hypertension with a .beta.-adrenergic blocker only is insufficient.
Prostanoic acid refers to the basic skeleton, shown by the formula below, as the common structural feature of the naturally occurring prostaglandins (hereinafter, prostaglandins are referred to as PGs). ##STR1## The primary PGs are classified based on the structural feature of the five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
Subscript 1--13,14-unsaturated-15-OH PA1 Subscript 2--5,6- and 13,14-diunsaturated 15-OH PA1 Subscript 3--5,6- 13,14- and 17,18-triunsaturated-15-OH PA1 (a) a .beta.-adrenergic blocker at the enhancement phase of aqueous humor production, and PA1 (b) a prostanoic acid compound at the suppression phase of aqueous humor production, in an amount effective in treatment of ocular hypertension.
Further, PGFs are sub-classified according to the configuration of hydroxy group at position 9 into .alpha.(hydroxy group being in the alpha configuration) and .beta.(hydroxy group being in the beta configuration).
The fact that the above compounds under item (b) have ocular hypotensive activity has been known by Japanese Patent Publication No. A-108/1990. It has also been described in Japanese Patent Publication No. A-313728/1988, page 7, column 3, line 7 from bottom to page 8, column 4, line 4, that a combination of PGF.sub.2 .alpha. isopropyl ester and Timolol (an agent for treating glaucoma) may be advantageous because the ocular hypotensive activity of the former is not inhibited by a .beta.-adrenergic blocker such as the latter. Furthermore, a synergistic combination of a .beta.-adrenergic blocker and a 13,14-dihydro-15-keto-PG is described in EP-A-458590 (Nov. 27, 1991). Such description, however, does not suggest that an alternate use of the .beta.-adrenergic blocker and the component (b) in the present invention gives an improved results.
After an extensive study the present inventor has surprisingly discovered that the prostanoic acid compounds exhibit a significant ocular hypotensive activity at the suppression phase of aqueous humor production in which the .beta.-adrenergic blockers such as Timolol can hardly exhibit the ocular hypotensive activity.